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Abstract
The occlusion of the middle cerebral artery was used as an experimental acute stroke model in 30 cats. The diffusion of water was followed by diffusion-sensitized MRI between 1 and 15 h after induction of stroke. It is demonstrated that images representing the trace of the diffusion tensor provide a much more accurate delineation of affected area than images representing the diffusion in one direction only. The reason is that the strong contrast caused by the anisotropy and orientation of myelin fibers is completely removed in the trace of the diffusion tensor. The trace images show a small contrast between white and gray matter. The diffusion coefficient of white matter is decreased in acute stroke to approximately the same extent as gray matter. It is further shown that the average lifetime of water in extra and intracellular space is shorter than 20 ms both for healthy and ischemic tissue indicating that myelin fibers are permeable to water. The anisotropy contrast did not change before or after induction of stroke, nor after sacrifice. Together, these observations are consistent with the view that the changes in water diffusion during acute stroke are directly related to cytotoxic oedema, i.e., to the change in relative volume of intra- and extracellular spaces. Changes in membrane permeability do not appear to contribute significantly to the changes in diffusion.
... Arguably the most impactful contribution of DWI is the highly sensitive detection of acute ischemia for emergency management of stroke 199 . By manually delineating the presence of hypersignal regions on DW images, one can obtain a rather accurate estimation of the volume of the lesion. ...
... patients of the acute stroke cohort had varying amounts of overly artifacted data, requiring the removal of certain vol- Moulton et al. NeuroImage 183 (2018) [186][187][188][189][190][191][192][193][194][195][196][197][198][199] Fractional Anisotropy (FA) and Axial Diffusivity (AD) maps were calculated from a tensor model estimated using FSL's DTIFIT . Fiber Orientation Distribution (FOD) volumes were computed by estimating response functions for the GM, WM, and CSF tissues for multi-shell multi-tissue constrained spherical deconvolution (MSMT-CSD) using a lmax of 4 . ...
... Here, FA-based registration is more precise when aligning the CST according to its FA values, E. Moulton et al. NeuroImage 183 (2018) [186][187][188][189][190][191][192][193][194][195][196][197][198][199] whereas diffusion-based registration is better at aligning the CST according to its diffusion orientation and amplitude (Irfanoglu et al., 2016;Wang et al., 2011). ANTs-FA is therefore incentivized to warp high FA values towards the center of the CST where densely-packed fibers aggregate and low FA values towards the edge of the tract or areas of crossing fibers in the centrum semiovale and corona radiata, where CST fiber density is low (Jones, 2008;Puig et al., 2017) ( Figs. 1 and 7). ...
Predicting motor, language, and global outcome after ischemic stroke is a major research concern. While initial impairment, age, and lesion volume have proven indicators of future outcome, the preservation of major white matter structures also play a role in these outcome domains. Diffusion tensor imaging (DTI) is sensitive to acute ischemic damage and can evaluate the integrity of important white matter bundles. Using a large cohort of patients who underwent a DTI protocol at 24 hours post-stroke and a clinical evaluation 3 months afterwards, the current thesis sought to (1) investigate spatial normalization strategies to optimally analyze imaging data, (2) establish which DTI parameter best predicts global outcome, and (3) determine if DTI can provide independent biomarkers of motor and language outcome. The major findings of the current thesis were: (1) fiber orientation distribution (FOD)-based spatial normalization performed similarly to scalar normalization for acute stroke data but yielded stronger anatomo-clinical correlations in subacute-chronic stroke patients, (2) axial diffusivity (AD) in the corona radiata highly contributes to the prediction of autonomy in patients, and (3) the AD of the corticospinal tract and arcuate fasciculus are independent markers of motor and aphasia outcome, respectively. These results support the use of AD for quantifying early brain damage in important white matter structures, such as the corona radiata, corticospinal tract, and arcuate fasciculus. These markers could be used for patient information, as surrogates of neuroprotective therapies at the hyperacute stage, or as stratification means for rehabilitative therapies.
... Various pathological states have been studied, mainly in white matter, such as demyelination (219), and stroke (16,248), using anisotropic diffusion imaging techniques. ...
... These scalar invariants are independent of the laboratory frame of reference and the direction or orientation of structures that reduce the observed diffusion anisotropy. Several scalar invariants have been proposed as MR imaging parameters of which the Trace (D) (13) is becoming an accepted imaging parameter in vivo (248). Trace (D) is proportional to the orientationally or isotropically averaged ADC and is given by the equation (12): ...
... The mechanism leading to DW-image contrast changes has been linked with temperature effects, an increase in restriction by membranes and cytotoxic oedema (2,25,248) or loss of high energy phosphates and an increase in EC potassium (39). ...
This thesis examines the relationship between certain magnetic resonance image (MRI) parameters and the properties of brain tissue studied in vitro. The importance of this derives from the fact that various pathological conditions of brain tissue in vivo can be identified using MRI protocols, but the relationship to underlying physiological changes is easier to study in vitro. The anoxia resistant turtle cerebellum is free of haemodynamic effects and responds to anisosmotic challenge as an osmometer. Apparatus was developed to maintain this preparation within a MRI magnet. Hypotonic solutions, causing cell swelling, led to decreases in apparent diffusion coefficient (ADC) and increases in the MR relaxation time T2; cell shrinking was associated with increases in ADC and decreases in T2. These effects were compared with simple models of the dynamics of tissue compartments, diffusion and relaxation. The ADC data fitted a two compartment model, with fast exchange between extracellular (EC) and intracellular (IC) space. The relaxation data are not well fitted in this way and seem to involve interaction between relaxation and compartment volumes. Directional differences of ADC were observed in relation to tissue micro- and macrostructure. The MRI measurements were weakly anisotropic, although with the available techniques it was not possible to assign the effects in a clear manner to the known oriented and layered arrays of cerebellar cells. Techniques were applied to separate the signals from EC and IC compartments, using (i) an EC contrast agent (Gd-DTPA), and (ii) imaging techniques in which MR sequence parameters influence the visibility of water in a compartment. A lower ADC observed in the presence of the contrast agent is consistent with the conclusions from other data that ADCIC<ADCEC although interpretation of the data may be complicated by intercompartmental exchange and susceptibility effects due to the contrast agent.
... Stroke induces neuronal beading and axonal swelling [4]. The affected brain regions appear as bright spots in diffusion-weighted images, because water diffusion is more restricted compared to healthy tissue [5]. DWI is also important for detecting and classifying lesions in the prostate [6,7] and female breast [8], effectively reducing the number of painful biopsies a patient has to endure. ...
... Objectively, this may be expressed in the contrast-to-noise ratio (CNR). In the context of DTI, a range of DAIs has been presented in attempts to improve tissue contrast (section 2. 5 ...
... DAIs and µDAIs were calculated according to the formalism described in sections 2. 5.1 and 2.5. 2. Volumetric RoIs were placed in the corpus callosum, the posterior limb of the capsula interna, the thalamus, and the frontal ventricle ( Fig. 3.7). ...
Diffusion-weighted magnetic resonance imaging with multidimensional diffusion encoding provides novel image contrasts to non-invasively study tissue microstructure. The subject of this thesis was the development of pulse sequences and optimization schemes for mul- tidimensional diffusion encoding. These methods were employed to study water diffusion in the human brain. A selection of parameters to quantify microscopic diffusion anisotropy were compared in terms of contrast-to-noise ratio in simulations with three characteristic diffusion tensor distributions. The simulation results indicate that the microscopic lattice index and the microscopic scaled relative anisotropy provide consistently high contrast-to-noise ratios. In discrepancy to the established theory, the simulation also showed that all investigated microscopic anisotropy parameters were affected by the orientation coherence of the diffusion tensor distribution. This finding is probably related to the second-order approximation of the signal attenuation in q-space trajectory imaging. Furthermore, the field strength dependence of the microscopic diffusion anisotropy was investigated. Higher diffusion anisotropy was measured at 7T compared to 3T. This effect was attributed to weaker signal attenuation with linear b-tensor encoding at 7T, whereas the signal attenuation with spherical b-tensor encoding was unaffected by a change in field strength. Based on biophysical models for water diffusion in the brain, these results are well explained by a shift in compartmental weighting between intra- and extra-axonal water. Experiments with oscillating diffusion gradients revealed the presence of diffusion time dependence in the brain for frequencies in the range of 0 to 30Hz. At shorter effective diffusion times, stronger signal attenuation and higher mean diffusivity estimates were measured. Approximately matching the frequency power spectrum of linear and spherical b-tensor encoding resulted in up to 50% lower anisotropic variance values, which indicates a strong bias in multidimensional b-tensor encoding depending on the frequency content of the applied diffusion gradients. In order to study long diffusion times between 50 and 500ms without affecting T 1 weight- ing, a pulse sequence featuring twice-refocused stimulated echoes was implemented. Ex- periments with a two-compartment phantom consisting of distilled water and paraffinum perliquidum demonstrated the ability of twice-refocused stimulated echoes to differentiate between time-dependent diffusion and compartmental T 1 relaxation. In vivo, diffusion time dependence of the axial and radial diffusivity was detected. The variance in T 1 val- ues appeared to be negligible in healthy white matter except in regions containing partial volumes of gray matter.
... 42 Some studies indicated that white matter DTI metrics were basically unchanged for diffusion times ranging from 8 to 2000 ms. [43][44][45][46] Other studies found changes with diffusion time. 38,40,41 It has been proposed that shorter diffusion times affect DTI metrics. ...
... Simulation data show significant decreases with effective diffusion time at constant b-value (λ ⊥ , MD) and at constant gradient strength (λ || , λ ⊥ , MD) similar to some studies [29][30][31][32][33][34][35][36][37][38][39][40][41] and differing from others. 25,[43][44][45][46] Previous studies have suggested that missing changes are due to having a constant b-value instead of constant gradient strength, which does not appear to be the case for these simulation data. Therefore, this lack of change in previously collected data could be due to T 2 effects. ...
... Nonetheless, the data do agree with some previous studies. 25,[43][44][45][46] All diffusivities measured in both grey and white matter significantly decreased with b-value when gradient strength or effective diffusion time was held constant. The difference in parameter values between grey and white matter also varied when gradient strength or effective diffusion time was held constant. ...
MRI and Monte Carlo simulated data of pulsed gradient spin echo experiments were used to study the effects of diffusion time, gradient strength and b-value on diffusion tensor (DT) metrics using real and simulated fixed rat spines. Radial (λ ⊥ ) in grey matter and simulation data, axial (λ || ) in both grey and white matter in fixed rat spinal cords and mean diffusivity in all tissues showed a significant decrease with diffusion time at b = 1 μm 2 /ms. All diffusivities significantly decreased with b-value at g = 116 mT/m and at Δ eff = 23 ms. The fractional anisotropy (FA) significantly increased with diffusion time at b = 1 μm 2 /ms in the simulation data and grey matter. FA significantly increased in white matter and simulation data and significantly decreased in grey matter with b-value at g = 116 mT/m and at Δ eff = 23 ms. These data suggest that DTI metrics are highly dependent on pulse sequence parameters.
... (Bihan, 1995). This technique provides a valuable tool to study brain microstructure and its alterations following injury (Parizel et al., 2005;To et al., 2022) and neurological disease (van Gelderen et al., 1994;Budde and Frank, 2010;Narvaez-Delgado et al., 2019). ...
... Given the importance of studying white matter tissue microstructure in vivo, several DW-MRI models have been proposed (e.g. Jelescu and Budde, 2017;Novikov et al., 2018Novikov et al., , 2019Assaf et al., 2004Assaf et al., , 2008Alexander et al., 2010;Dyrby et al., 2011;Veraart et al., 2021;Neuman, 1974;van Gelderen et al., 1994;Murday and Cotts, 1968;Söderman and Jönsson, 1995;Lee et al., 2020). However, validating these noninvasive techniques requires physical and numerical phantoms with a well-known microstructure (Lavdas et al., 2013;Campbell et al., 2005;Fillard et al., 2011;Tournier et al., 2008;Fieremans et al., 2008;Schilling et al., 2019;Zhou et al., 2018;Maier-Hein et al., 2017;Andersson et al., 2020;Lee et al., 2020;Rafael-Patino et al., 2020). ...
Monte-Carlo diffusion simulations are a powerful tool for validating tissue microstructure models by generating synthetic diffusion-weighted magnetic resonance images (DW-MRI) in controlled environments. This is fundamental for understanding the link between micrometre-scale tissue properties and DW-MRI signals measured at the millimetre-scale, optimising acquisition protocols to target microstructure properties of interest, and exploring the robustness and accuracy of estimation methods. However, accurate simulations require substrates that reflect the main microstructural features of the studied tissue. To address this challenge, we introduce a novel computational workflow, CACTUS (Computational Axonal Configurator for Tailored and Ultradense Substrates), for generating synthetic white matter substrates. Our approach allows constructing substrates with higher packing density than existing methods, up to 95 % intra-axonal volume fraction, and larger voxel sizes of up to (500um) 3 with rich fibre complexity. CACTUS generates bundles with angular dispersion, bundle crossings, and variations along the fibres of their inner and outer radii and g-ratio. We achieve this by introducing a novel global cost function and a fibre radial growth approach that allows substrates to match predefined targeted characteristics and mirror those reported in histological studies. CACTUS improves the development of complex synthetic substrates, paving the way for future applications in microstructure imaging.
... frequency across an axon cross-section. For practically relevant case of wide-pulsed gradients, when gradient duration δ exceeds the time to diffuse across axon radius r, signal attenuation can be interpreted as transverse relaxation , − ln S ∼ R * 2 · 2δ, occurring during the net pulse duration 2δ, with the rate R * 2 ∝ r 4 that is strongly sensitive to the radius (Neuman, 1974;van Gelderen et al., 1994). This signal sensitivity is further weighted by the axon volume ∝ r 2 , leading to the effective MR axon radius r eff calculated based on the equivalent circle radius r (Burcaw et al., 2015;Sepehrband et al., 2016;Lee et al., 2020a;Veraart et al., 2020): ...
... with intrinsic diffusivity D 0 fixed at 2 µm 2 /ms, matching the value in simulations. Eq. (9) is applicable in the wide pulse limit, i.e., δ ≫ r 2 /D 0 (Neuman, 1974;van Gelderen et al., 1994). Given that the effective axon radius is about 1 µm in histology (dominated by the tail of axon radius distribution, Eq. (1) and Figure 2a), the pulse width δ = 10 ms is indeed much longer than the correlation time r 2 /D 0 ∼ 0.5 ms. ...
We consider the effect of non-cylindrical axonal shape on axonal diameter mapping with diffusion MRI. Practical sensitivity to axon diameter is attained at strong diffusion weightings b, where the deviation from the 1/radical b scaling yields the finite transverse diffusivity, which is then translated into axon diameter. While axons are usually modeled as perfectly straight, impermeable cylinders, the local variations in diameter (caliber variation or beading) and direction (undulation) have been observed in microscopy data of human axons. Here we quantify the influence of cellular-level features such as caliber variation and undulation on axon diameter estimation. For that, we simulate the diffusion MRI signal in realistic axons segmented from 3-dimensional electron microscopy of a human brain sample. We then create artificial fibers with the same features and tune the amplitude of their caliber variations and undulations. Numerical simulations of diffusion in fibers with such tunable features show that caliber variations and undulations result in under- and over-estimation of axon diameters, correspondingly; this bias can be as large as 100%. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.
... DWI and related techniques are used extensively for brain and whole-body imaging [14]. Common applications of this contrast mechanism include tumor imaging to examine diffusion restriction (tumor cellularity) [15,16], stroke imaging [17,18], and anisotropy of white matter fiber bundles in the brain [17][18][19][20][21]. Less common applications are studies of cardiac muscle [22] and vascular structure. With long diffusion imaging scan times, free molecules move out-of-phase via Brownian motion, resulting in signal attenuation, while the restriction of molecular motion results in signal retention. ...
... DWI and related techniques are used extensively for brain and whole-body imaging [14]. Common applications of this contrast mechanism include tumor imaging to examine diffusion restriction (tumor cellularity) [15,16], stroke imaging [17,18], and anisotropy of white matter fiber bundles in the brain [17][18][19][20][21]. Less common applications are studies of cardiac muscle [22] and vascular structure. ...
Background
Atherosclerosis is an arterial vessel wall disease characterized by slow, progressive lipid accumulation, smooth muscle disorganization, and inflammatory infiltration. Atherosclerosis often remains subclinical until extensive inflammatory injury promotes vulnerability of the atherosclerotic plaque to rupture with luminal thrombosis, which can cause the acute event of myocardial infarction or stroke. Current bioimaging techniques are unable to capture the pathognomonic distribution of cellular elements of the plaque and thus cannot accurately define its structural disorganization.
Methods
We applied cardiovascular magnetic resonance spectroscopy (CMRS) and diffusion weighted CMR (DWI) with generalized Q-space imaging (GQI) analysis to architecturally define features of atheroma and correlated these to the microscopic distribution of vascular smooth muscle cells (SMC), immune cells, extracellular matrix (ECM) fibers, thrombus, and cholesteryl esters (CE). We compared rabbits with normal chow diet and cholesterol-fed rabbits with endothelial balloon injury, which accelerates atherosclerosis and produces advanced rupture-prone plaques, in a well-validated rabbit model of human atherosclerosis.
Results
Our methods revealed new structural properties of advanced atherosclerosis incorporating SMC and lipid distributions. GQI with tractography portrayed the locations of these components across the atherosclerotic vessel wall and differentiated multi-level organization of normal, pro-inflammatory cellular phenotypes, or thrombus. Moreover, the locations of CE were differentiated from cellular constituents by their higher restrictive diffusion properties, which permitted chemical confirmation of CE by high field voxel-guided CMRS.
Conclusions
GQI with tractography is a new method for atherosclerosis imaging that defines a pathological architectural signature for the atheromatous plaque composed of distributed SMC, ECM, inflammatory cells, and thrombus and lipid. This provides a detailed transmural map of normal and inflamed vessel walls in the setting of atherosclerosis that has not been previously achieved using traditional CMR techniques. Although this is an ex-vivo study, detection of micro and mesoscale level vascular destabilization as enabled by GQI with tractography could increase the accuracy of diagnosis and assessment of treatment outcomes in individuals with atherosclerosis.
... Previous studies suggest that this technique may have a potential for registration of cell density and necrosis in tumors. Much knowledge of tissue ADCs has come from experimental studies investigating the usefulness of DWI to detect early effects of ischemia on brain tissue (e.g., [13][14][15][16][17][18]. A reduction in ADC up to 50% occurs immediately after induction of ischemia. ...
... A reduction in ADC up to 50% occurs immediately after induction of ischemia. Several reasons for this reduction have been proposed; e.g., swelling of cells, leading to changes in the relative volume of the intra-and extracellular compartments, and interruption of molecular movement in the intracellular compartment due to energy depletion during cell injury (14,15). The factors important for ADCs of tumors may, however, be different from those determining the ADCs of normal tissues. ...
The aim of this study was to investigate whether apparent diffusion coefficients (ADCs) could be used as measures of cell density and necrotic fraction of tumors. Tumors of four human melanoma xenograft lines were subjected to diffusion‐weighted magnetic resonance imaging (DWI). ADCs were calculated from the images and related to cell density and necrotic fraction, as determined from histological sections. A significant correlation was found between the ADC of the viable tissue and cell density, regardless of whether tumors of different lines or different regions within individual tumors were considered. Necrosis was found in two of the lines. A single region of massive necrosis that could be differentiated from the viable tissue in ADC maps was found in one line, whereas a number of smaller necrotic regions that could not be identified in ADC maps were found in the other line. Tumor ADC was significantly correlated with the necrotic fraction of the former, but not of the latter line. Our results suggest that ADCs can be used as measures of cell density and necrotic fraction of some but not of all tumors, depending on whether the individual necrotic regions are large enough to be differentiated from the viable tissue with the obtained spatial resolution of the DW images. Magn Reson Med 43:828–836, 2000. © 2000 Wiley‐Liss, Inc.
... To compare the degree of anisotropy in each parameter, an anisotropy index (AI) proposed by van Gelderen (23) was calculated in each case. Although this index is not truly quantitative, in the sense that it is not rotationally invariant, it provides useful information when the fiber direction is approximately aligned with the gradient axes, as is the case in the internal capsule. ...
... Although the discrepancy between the intra-and extracellular volume fractions and the slow and fast diffusion fractions has yet to be resolved, it is worth noting the similarity between ADC fast and the ADC for the extracel- The ADC value is obtained from a linear fit using data acquired with the first 11 points up to b ϭ 1000 s mm Ϫ2 only. The AI represents the anisotropy index calculated from the squared deviations of the ADC along three orthogonal directions as described by van Gelderen et al. (23). The ADC values are reported in units ϫ 10 Ϫ3 mm 2 s Ϫ1 . ...
Biexponential diffusion decay is demonstrated in the human brain in vivo using b factors up to 4000 sec mm⁻². Fitting of the signal decay data yields values for the slow and fast diffusion components and volume fractions in agreement with previous studies in rat and human brain. In addition, differences in the fitted parameters are demonstrated in the white and gray matter and diffusion anisotropy is demonstrated in both the slow and fast diffusing components. Apparent anisotropy in the component fractions is discussed in terms of directionally dependent exchange rates between the compartments. The lack of a relationship between the estimated contribution to the signal of the fast and slow components and echo time appears to rule out T2 differences in the observed water compartments. Values obtained for the fast diffusion coefficient, including differences between white and gray matter and the degree of anisotropy are compatible with the predictions of extracellular diffusion of water based on tortuosity models and the diffusion of tetramethylammonium ions in rat brain. Magn Reson Med 44:852–859, 2000. © 2000 Wiley‐Liss, Inc.
... Although CT is still the preferred imaging modality in the early management of acute stroke, MRI with DW measure is more sensitive than noncontrast CT for the very early detection of acute ischemia and is shown to be more efficient than the first CT, second CT and MRI in the evaluation of patients who are presented within the 24 h [43]. The main reason for this accuracy is the capability of the DW imaging to show the slight differences in diffusion of the water molecules across the membranes during the cytotoxic edema; therefore, more visually available contrast will be presented in contrast to CT imaging which requires significant amount water molecule activity and retention and more time to exhibit detectable contrasts [44,45]. However, not all medical centers have convenient access to MRI, and due to patient contraindications and intolerance to MRI scans, the amount of time it takes, and despite providing more accurate insight in tissue and vascular pathology, CT is considered the first-line imaging study at most centers [46]. ...
Stroke is a serious health condition that is responsible for more than 5% of total deaths. Near 20% of patients experiencing stroke die every year, resulting in the stroke being at the top of the list of preventable causes of death. Once an acute stroke is suspected, a golden hour of less than an hour is available to prevent the undesirable consequences. Since neuroimaging is mandatory in the diagnosis of stroke, the proper use of neuroimaging could help saving time and planning the right treatment for the patient. Some of the available imaging methods help us with rapid results, while others benefit us from a more accurate diagnosis. Hereby, we aim to provide a clinical review of the advantages and disadvantages of different available neuroimaging methods in approaching acute stroke to help clinicians choose the best method according to the settings.
... Hücre içine su girişine bağlı hücreler arası hacim azalır. Ayrıca mikrotübüllerin hasarı ve hücresel bileşenlerin de parçalanmasına bağlı hücre içi viskozite artışı, sitoplazmik hareket azalması, ısı, hücre membranında geçirgenlik değişimi gibi etkenler difüzyon kısıtlanmasına katkıda bulunur [6]. ...
... This source of ambiguity can be avoided by using the rotationally invariant Tr (D ). Furtherm ore, it has been suggested that the use of Tr (D) maps may improve definition of ischaemic lesion contrast by rem oving the confounding effects of diffusion anisotropy (van Gelderen et al., 1994) (see Fig. 2.9). This has been recently evaluated in a rat model of focal ischaemia, where a significant disagreement was found between the lesion delineated by a unidirectional ADC measurement and that delineated using the trace (Lythgoe et al., 1997). ...
Two MRI techniques, namely diffusion and perfusion imaging, are becoming increasingly used for evaluation of the pathophysiology of stroke. This work describes the use of these techniques, together with more conventional MRI modalities (such as T1, and T2 imaging) in the investigation of cerebral ischaemia. The work was performed both in a paediatric population in a whole-body clinical MR system (1.5 T) and in an animal model of focal ischaemia at high magnetic field strength (8.5 T). For the paediatric studies, a single shot echo planar imaging (EPI) sequence was developed to enable the on-line calculation of maps of the trace of the diffusion tensor. In the process of this development, it was necessary to address two different imaging artefacts in these maps: eddy current induced image shifts, and residual Nyquist ghost artefacts. Perfusion imaging was implemented using an EPI sequence to follow the passage through the brain of a bolus of a paramagnetic contrast agent. Computer simulations were performed to evaluate the limitations of this technique in the quantification of cerebral blood flow when delay in the arrival and dispersion of the bolus of contrast agent are not accounted for. These MRI techniques were applied to paediatric patients to identify acute ischaemic events, as well as to differentiate between multiple acute events, or between acute and chronic events. Furthermore, the diffusion and perfusion findings were shown to contribute significantly to the management of patients with high risk of stroke, and in the evaluation of treatment outcome. In the animal experiments, permanent middle cerebral artery occlusion was performed in rats to investigate longitudinally the acute MRI changes (first 4-6 hours) following an ischaemic event. This longitudinal analysis contributed to the understanding of the evolution of the ischaemic lesion. Furthermore, the findings allowed the acute identification of tissue 'at risk' of infarction.
... При постпроцесинга на DWI образите се генерират: дифузионни образи, dwi trace и ADC карти, които са еквивалентни. На дифузионните образи лезии с рестрикция на дифузията на водата са хиперинтенсни спря-мо нормалната тъкан, докато на ADC картите са хипоинтенсни (8). ADC картите премахват T2 shine through ефекта. ...
... The very first works in this area began with post-mortem tissue (Schulz et al., 1980). The non-invasive nature of diffusion MRI makes it feasible to study brain microstructure in healthy volunteers as well as patients (van Gelderen et al., 1994;Fazekas et al., 1987;Shenton et al., 1992). The acquisition of data on a population is possible and therefore group analysis studies are feasible (Afzali et al., 2011). ...
Diffusion MRI is a non-invasive technique to study brain microstructure. Differences in the microstructural properties of tissue, including size and anisotropy, can be represented in the signal if the appropriate method of acquisition is used. However, to depict the underlying properties, special care must be taken when designing the acquisition protocol as any changes in the procedure might impact on quantitative measurements. This work reviews state-of-the-art methods for studying brain microstructure using diffusion MRI and their sensitivity to microstructural differences and various experimental factors. Microstructural properties of the tissue at a micrometer scale can be linked to the diffusion signal at a millimeter-scale using modeling. In this paper, we first give an introduction to diffusion MRI and different encoding schemes. Then, signal representation-based methods and multi-compartment models are explained briefly. The sensitivity of the diffusion MRI signal to the microstructural components and the effects of curvedness of axonal trajectories on the diffusion signal are reviewed. Factors that impact on the quality (accuracy and precision) of derived metrics are then reviewed, including the impact of random noise, and variations in the acquisition parameters (i.e., number of sampled signals, b-value and number of acquisition shells). Finally, yet importantly, typical approaches to deal with experimental factors are depicted, including unbiased measures and harmonization. We conclude the review with some future directions and recommendations on this topic.
... CLARITY PI staining revealed that several areas connected to the stroke core, some remote to the lesion, were affected at the acute stage ( Fig. 4b-d). At the macroscopic level, quantitative T2 values in the stroke region were substantially increased while MD values were decreased (Fig. 3c, d) due to a shift in water composition (e.g., the bound versus free water ratio), changes due to cytotoxic edema, and relative volume differences of intracellular and extracellular spaces 47 . The stroke mask used for CLARITY analysis was based on the hyperintense area in the T2-weighted MRI, which is expected to correspond to histology-based lesion at that time point 48,49 . ...
3D histology, slice-based connectivity atlases, and diffusion MRI are common techniques to map brain wiring. While there are many modality-specific tools to process these data, there is a lack of integration across modalities. We develop an automated resource that combines histologically cleared volumes with connectivity atlases and MRI, enabling the analysis of histological features across multiple fiber tracts and networks, and their correlation with in-vivo biomarkers. We apply our pipeline in a murine stroke model, demonstrating not only strong correspondence between MRI abnormalities and CLARITY-tissue staining, but also uncovering acute cellular effects in areas connected to the ischemic core. We provide improved maps of connectivity by quantifying projection terminals from CLARITY viral injections, and integrate diffusion MRI with CLARITY viral tracing to compare connectivity maps across scales. Finally, we demonstrate tract-level histological changes of stroke through this multimodal integration. This resource can propel investigations of network alterations underlying neurological disorders.
... Various studies have used STE to study the time dependence of diffusion in the brain, reporting conflicting results. No time dependence was observed in feline brain tissue over a wide range of diffusion times ranging from 20 ms up to 2000 ms 18 and in human corticospinal tract in vivo for Δ between 64 and 256 ms. 19 In contrast, diffusion was found to be time dependent in bovine optic nerve, rat spinal cord, and rat brain for diffusion times between 40 ms and 250 ms. ...
Purpose
Diffusion times longer than 50 ms are typically probed with stimulated‐echo sequences. Varying the diffusion time in stimulated‐echo sequences affects the T1 weighting of subcompartments, complicating the analysis of diffusion time dependence. Although inversion recovery preparation could be used to change the T1 weighting, it cannot ensure equal T1 weighting at arbitrary mixing times. In this article, a sequence that ensures constant T1 weighting over a wide range of diffusion times is presented.
Methods
The proposed sequence features 2 independent longitudinal storage periods: TM1 and TM2. Diffusion encoding is performed during TM1, effectively coupling the diffusion time and TM1. Equal T1 weighting at arbitrary diffusion times is realized by keeping the total mixing time TM1 + TM2 constant. The sequence was compared with conventional stimulated‐echo measurements of diffusion in a 2‐compartment phantom consisting of distilled water and paraffinum perliquidum. Additionally, in vivo DTI of the brain was carried out for 8 healthy volunteers with diffusion times ranging from 50 to 500 ms.
Results
Diffusion time dependence of the axial and radial diffusivity was detected in the brain. Both sequences resulted in almost identical diffusivities in white matter. In regions containing partial volumes of gray and white matter, a dependency on T1 weighting was observed.
Conclusion
In accordance with previous studies, little variance of T1 values appeared to be present in healthy white matter. However, this is likely different in diseased tissue. Here, the proposed sequence can be effective in differentiating between diffusion time dependence and T1 weighting effects.
... CTP provides detailed information about blood flow within the brain and can determine areas that are (in)adequately perfused with blood. However, CTP has a lower signal to noise ratio compared to DWI where infarcted core brain tissue readily shows up as hyperintense regions [14], [21]. ...
Infarcted brain tissue resulting from acute stroke readily shows up as hyperintense regions within diffusion-weighted magnetic resonance imaging (DWI). It has also been proposed that computed tomography perfusion (CTP) could alternatively be used to triage stroke patients, given improvements in speed and availability, as well as reduced cost. However, CTP has a lower signal to noise ratio compared to MR. In this work, we investigate whether a conditional mapping can be learned by a generative adversarial network to map CTP inputs to generated MR DWI that more clearly delineates hyperintense regions due to ischemic stroke. We detail the architectures of the generator and discriminator and describe the training process used to perform image-to-image translation from multi-modal CT perfusion maps to diffusion weighted MR outputs. We evaluate the results both qualitatively by visual comparison of generated MR to ground truth, as well as quantitatively by training fully convolutional neural networks that make use of generated MR data inputs to perform ischemic stroke lesion segmentation. Segmentation networks trained using generated CT-to-MR inputs result in at least some improvement on all metrics used for evaluation, compared with networks that only use CT perfusion input.
... √ van Gelderen et al. (1994;van Everdingen et al., 1998;Warach et al., 1995;Kamalian et al., 2011) Diffusion in chronic stroke and √ Wardlaw et al. (2013;Schaefer et al., small vessel disease. 2000;Hachinski et al., 2006) Diffusion imaging in brain tumors. ...
The brain network is the function of a structurally and functionally organized complex system. Its structure and activity analysis is one of the most significant challenges. The graph based techniques of brain complex networks have been successfully used in various types of image and medical data analysis. In this survey paper, we focus on a comprehensive study of the analytical methods for complex brain network based on graph theory. This review paper is intended to provide automated brain disease diagnosis based on functional and diffusional MRI modalities. Furthermore, we discuss subjective and objective quality evaluations of complex brain networks, important tools for automated brain disease diagnosis, challenging issues and future research directions in this increasingly evolving research field.
... Diffusion tensor imaging (DTI) is a useful MRI technique that can reflect the structural integrity and interstitial space of the white matter by detecting the directionality of extracellular water diffusion [fractional anisotropy (FA)] and of free water diffusion [mean diffusivity (MD)] and has been applied to evaluate white matter damage in iNPH [93][94][95][96]. Some authors have confirmed that after shunt surgery in patients presenting iNPH, the fractional anisotropy (FA) in the corona radiata decreases, and the regions involved were located between the enlarged lateral ventricles and Sylvian fissures. ...
... To explore evidence of glymphatic clearance in the human being during sleep, here we tested the hypothesis that water diffusivity (as assessed by diffusion MRI) would be increased during sleep compared to the awake state. Our hypothesis is based on the observation that in rodents, cortical ISF volume increases (~40%) during sleep and is a major determinant of glymphatic transport efficiency (Kress et al., 2014;Xie et al., 2013); and further, that quantitative diffusion MRI is sensitive to changes in ISF volume (Benveniste et al., 1992;Davis et al., 1994;Sotak, 2004; van Gelderen et al., 1994;Verheul et al., 1994). We hypothesized that during sleep, ISF volume will expand thereby enhancing entry of CSF into the brain when compared to the awake M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 4 state. ...
... In DWI, the ischemic lesion appears hypointense, consistent with a decrease in the apparent diffusion coefficient of water (ADC), which is a weighted average between the intracellular (assumed to be lower) and extracellular diffusion coefficients (assumed to be higher). The decrease in ADC reflects the changes in the ratio of intracellular and extracellular volume, because ischemia-induced energy impairment and membrane pump failure allow the osmotic drainage of water from extracellular to intracellular spaces that leads to cytotoxic edema (van Gelderen et al., 1994). The results obtained in control animals ( Figure S4A) showed that in males, the damaged area at 24 and 48 hr was larger than in females, which is in line with previous reports (Spychala et al., 2017). ...
Sex has a role in the incidence and outcome of neurological illnesses, also influencing the response to treatments. Neuroinflammation is involved in the onset and progression of several neurological diseases, and the fact that estrogens have anti-inflammatory activity suggests that these hormones may be a determinant in the sex-dependent manifestation of brain pathologies. We describe significant differences in the transcriptome of adult male and female microglia, possibly originating from perinatal exposure to sex steroids. Microglia isolated from adult brains maintain the sex-specific features when put in culture or transplanted in the brain of the opposite sex. Female microglia are neuroprotective because they restrict the damage caused by acute focal cerebral ischemia. This study therefore provides insight into a distinct perspective on the mechanisms underscoring a sexual bias in the susceptibility to brain diseases.
... 16 This is in keeping with previously identified challenges of global measures of whole brain volume introduced by effects in regions remote from infarction, including noise, resorption of parenchymal extracellular fluid, and displacement of cerebral blood volume. 15,31 In contrast, AD defined by nonlinear registration is a direct estimation of local distortion, and, therefore, any errors are likely to be proportional to the infarct volume. ...
Background and Purpose
Lesion expansion in the week following acute stroke involves both infarct growth and anatomical distortion due to edema and hemorrhage. Enabling separate quantification would allow clinical trials targeting these distinct pathological processes. We developed an objective and automated approach to quantify these processes at 24-hours and 1-week.
Methods
Patients with acute ischemic stroke were scanned at presentation, 24-hours and 1-week in a magnetic resonance imaging (MRI) cohort study. Infarct growth and anatomical distortion were calculated from follow up lesion masks after linear and non-linear registration to a presenting MRI scan. Performance of infarct growth and anatomical distortion was compared to edema quantified using cerebrospinal fluid displacement. The utility of alternative reference images to define anatomical distortion, including template MRI, mirrored MRI and presenting computed tomography (CT) scan, was explored.
Results
Thirty-seven patients with non-lacunar stroke were included. Anatomical distortion was responsible for 20% and 36% of lesion expansion at 24-hours (n=30) and 1-week (n=28). Registration-defined infarct growth and anatomical distortion compared favorably with edema quantified using cerebrospinal fluid displacement, particularly at smaller infarct volumes. Presenting CT imaging was the preferred alternative reference image to presenting MRI for measuring anatomical distortion.
Conclusions
The contributions of infarct growth and anatomical distortion to lesion expansion can be measured separately over time through the use of image registration. This approach can be used to combine imaging outcome data from CT and MRI.
... Because of this structure, the diffusion coefficient is approximated by a full nine-element tensor (with six independent elements). The full tensor can be measured either with diffusion gradients applied in at least six directions, or with a rotational invariant parameter of D, such as the trace of the tensor [40,41]. Since the diffusion depends on the tissue structure, it can also change significantly and become nonlinear when tissue properties change. ...
This chapter considers the mechanism of measuring temperature and temperature changes with magnetic resonance imaging (MRI). It first covers the basic principles and physics of MRI, and in more detail how the MRI signal is generated, detected, and localized using weak spatially varying magnetic fields called gradient fields. The chapter also covers magnetic resonance temperature imaging (MRTI) in detail. All currently used methods of MRTI, such as the proton resonance frequency shift (PRFS) method and the temperature dependence of the T1 and T2 relaxations times, are discussed. T2‐based thermometry has recently been used in vivo to monitor the temperature in subcutaneous fat during MR‐guided focused ultrasound treatments of uterine fibroids. Magnetic resonance spectroscopic imaging (MRSI) temperature measurement methods are based on the concept that the separation of peaks from different tissue components in a frequency spectrum is a function of temperature. The chapter concludes by discussing some practical MRTI considerations.
... √ van Gelderen et al. (1994;van Everdingen et al., 1998;Warach et al., 1995;Kamalian et al., 2011) Diffusion in chronic stroke and √ Wardlaw et al. (2013;Schaefer et al., small vessel disease. 2000;Hachinski et al., 2006) Diffusion imaging in brain tumors. ...
... Fortuitously, the typical time-scales of diffusion encodings are compatible with the time required for water molecules to traverse (sub)cellular length scales at 37 °C. Thus, water diffusion is sensitive to structures on a spatial scale much smaller than the voxel size, an advantage that found applications abound, for example, in early detection of stroke (10)(11)(12) as well as in fiber orientation mapping and tracking (13,14) as well as other applications in biomedicine (15). ...
Many developmental processes, such as plasticity and aging, or pathological processes such as neurological diseases are characterized by modulations of specific cellular types and their microstructures. Diffusion-weighted Magnetic Resonance Imaging (DW-MRI) is a powerful technique for probing microstructure, yet its information arises from the ubiquitous, non-specific water signal. By contrast, diffusion-weighted Magnetic Resonance Spectroscopy (DW-MRS) allows specific characterizations of tissues such as brain and muscle in vivo by quantifying the diffusion properties of MR-observable metabolites. Many brain metabolites are predominantly intracellular, and some of them are preferentially localized in specific brain cell populations, e.g., neurons and glia. Given the microstructural sensitivity of diffusion-encoding filters, investigation of metabolite diffusion properties using DW-MRS can thus provide exclusive cell and compartment-specific information. Furthermore, since many models and assumptions are used for quantification of water diffusion, metabolite diffusion may serve to generate a-priori information for model selection in DW-MRI. However, DW-MRS measurements are extremely challenging, from the acquisition to the accurate and correct analysis and quantification stages. In this review, we survey the state-of-the-art methods that have been developed for the robust acquisition, quantification and analysis of DW-MRS data and discuss the potential relevance of DW-MRS for elucidating brain microstructure in vivo. The review highlights that when accurate data on the diffusion of multiple metabolites is combined with accurate computational and geometrical modelling, DW-MRS can provide unique cell-specific information on the intracellular structure of brain tissue, in health and disease, which could serve as incentives for further application in vivo in human research and clinical MRI.
... The diffusion coefficient is thus described by a full tensor containing nine elements. For temperature MRI based on D, either the tensor should be measured, or rotationally invariant parameters of D should be measured such as the trace of the tensor (49,50). Such measurements take more time than an acquisition with different weighting in a single direction. ...
Continuous thermometry during a hyperthermic procedure may help to correct for local differences in heat conduction and energy absorption, and thus allow optimization of the thermal therapy. Noninvasive, three-dimensional mapping of temperature changes is feasible with magnetic resonance (MR) and may be based on the relaxation time T1, the diffusion coefficient (D), or proton resonance frequency (PRF) of tissue water. The use of temperature-sensitive contrast agents and proton spectroscopic imaging can provide absolute temperature measurements. The principles and performance of these methods are reviewed in this paper. The excellent linearity and near-independence with respect to tissue type, together with good temperature sensitivity, make PRF-based temperature MRI the preferred choice for many applications at mid to high field strength (≥ 1 T). The PRF methods employ radiofrequency spoiled gradient-echo imaging methods. A standard deviation of less than 1°C, for a temporal resolution below 1 second and a spatial resolution of about 2 mm, is feasible for a single slice for immobile tissues. Corrections should be made for temperature-induced susceptibility effects in the PRF method. If spin-echo methods are preferred, for example when field homogeneity is poor due to small ferromagnetic parts in the needle, the D- and T1-based methods may give better results. The sensitivity of the D method is higher that that of the T1 methods provided that motion artifacts are avoided and the trace of D is evaluated. Fat suppression is necessary for most tissues when T1, D, or PRF methods are employed. The latter three methods require excellent registration to correct for displacements between scans. J. Magn. Reson. Imaging 2000;12:525–533. © 2000 Wiley-Liss, Inc.
... Neuropathological findings in idiopathic normal pressure hydrocephalus (INPH) are generally consistent with white matter damage, regardless of the underlying, yet unknown, pathophysiological mechanisms involved in INPH [1][2][3][4][5]. Diffusion tensor imaging (DTI) has recently been applied to evaluate white matter damage in INPH because DTI is a useful MRI technique that can reflect the structural integrity and interstitial space of the white matter by detecting the directionality of extracellular water diffusion [fractional anisotropy (FA)] and of free water diffusion [mean diffusivity (MD)] [6][7][8][9]. However, it has been found that these DTI indices could not only reflect the microstructural damage of fibres, such as axonal degeneration or ischaemic demyelination, which is generally represented by a low FA value, because several recent DTI studies reported that FA values of the periventricular corticospinal tract (CST) in INPH patients were higher compared to those in healthy controls [10][11][12]. ...
Background
The aim of this study was to elucidate changes in cerebral white matter after shunt surgery in idiopathic normal pressure hydrocephalus (INPH) using diffusion tensor imaging (DTI).
Methods
Twenty-eight consecutive INPH patients whose symptoms were followed for 1 year after shunt placement and 10 healthy control (HC) subjects were enrolled. Twenty of the initial 28 INPH patients were shunt-responsive (SR) and the other 8 patients were non-responsive (SNR). The cerebral white matter integrity was detected by assessing fractional anisotropy (FA) and mean diffusivity (MD). The mean hemispheric DTI indices and the ventricular sizes were calculated, and a map of these DTI indices was created for each subject. The DTI maps were analysed to compare preshunt INPH with HC and preshunt INPH with 1 year after shunt placement in each INPH group, using tract-based spatial statistics. We restricted analyses to the left hemisphere because of shunt valve artefacts.
Results
The ventricles became significantly smaller after shunt placement both in the SR and SNR groups. In addition, there was a significant interaction between clinical improvement after shunt and decrease in ventricular size. Although the hemispheric DTI indices were not significantly changed after shunt placement, there was a significant interaction between clinical improvement and increase in hemispheric MD. Compared with the HC group, FA in the corpus callosum and in the subcortical white matter of the convexity and the occipital cortex was significantly lower in SR at baseline, whereas MD in the periventricular and peri-Sylvian white matter was significantly higher in the SR group. Compared with the pre-operative images, the post-operative FA was only decreased in the corona radiata and only in the SR group. There were no significant regions in which DTI indices were altered after shunt placement in the SNR group.
Conclusions
Brain white matter regions in which FA was decreased after shunt placement were in the corona radiata between the lateral ventricles and the Sylvian fissures. This finding was observed only in shunt-responsive INPH patients and might reflect the plasticity of the brain for mechanical pressure changes from the cerebrospinal fluid system.
Electronic supplementary material
The online version of this article (doi:10.1186/s12987-016-0048-8) contains supplementary material, which is available to authorized users.
... The subsequent increase in ADC results in neuropil fragmentation and the consequent loss of diffusion barriers. T 2 -weighted signal is mostly due to the fragmentation of the previously swollen neuropil [i.e., an increase of free water in the tissue (18)(19)(20)]. ...
Summary: Purpose: Patients with temporal lobe epilepsy (TLE) usually had an initial precipitating injury in early childhood. However, epilepsy does not develop in all children who have undergone an early insult. As in patients, the consequences of the lithium-pilocarpine-induced status epilepticus (SE) are age dependent, and only a subset of 21-day-old rats will develop epilepsy. Thus with magnetic resonance imaging (MRI), we explored the differences in the evolution of lesions in these two populations of rats.
Methods: SE was induced in 21-day-old rats by the injection of lithium and pilocarpine. T2-weighted images and T2 relaxation-time measurements were used for detection of lesions from 6 h to 4 months after SE.
Results: Three populations of rats could be distinguished. The first one had neither MRI anomalies nor modification of the T2 relaxation time, and these rats did not develop epilepsy. In the second one, a hypersignal appeared at the level of the piriform and entorhinal cortices 24 h after SE (increase of 49% of the T2 relaxation time in the piriform cortex) that began to disappear 48–72 h after SE; epilepsy developed in all these animals. The third population of rats showed a more moderate increase of the T2 relaxation time in cortices (14% in the piriform cortex) that could not be seen on T2-weighted images. Epilepsy developed in all these rats. Only in a subpopulation of the 21-day-old rats with epilepsy did hippocampal sclerosis develop.
Conclusions: These results suggest that the injury of the piriform and entorhinal cortices during SE play a critical role for the installation of the epileptic networks and the development of epilepsy.
The increasing availability of high‐performance gradient systems in human MRI scanners has generated great interest in diffusion microstructural imaging applications such as axonal diameter mapping. Practically, sensitivity to axon diameter in diffusion MRI is attained at strong diffusion weightings , where the deviation from the expected scaling in white matter yields a finite transverse diffusivity, which is then translated into an axon diameter estimate. While axons are usually modeled as perfectly straight, impermeable cylinders, local variations in diameter (caliber variation or beading) and direction (undulation) are known to influence axonal diameter estimates and have been observed in microscopy data of human axons. In this study, we performed Monte Carlo simulations of diffusion in axons reconstructed from three‐dimensional electron microscopy of a human temporal lobe specimen using simulated sequence parameters matched to the maximal gradient strength of the next‐generation Connectome 2.0 human MRI scanner ( 500 mT/m). We show that axon diameter estimation is accurate for nonbeaded, nonundulating fibers; however, in fibers with caliber variations and undulations, the axon diameter is heavily underestimated due to caliber variations, and this effect overshadows the known overestimation of the axon diameter due to undulations. This unexpected underestimation may originate from variations in the coarse‐grained axial diffusivity due to caliber variations. Given that increased axonal beading and undulations have been observed in pathological tissues, such as traumatic brain injury and ischemia, the interpretation of axon diameter alterations in pathology may be significantly confounded.
Monte-Carlo diffusion simulations are a powerful tool for validating tissue microstructure models by generating synthetic diffusion-weighted magnetic resonance images (DW-MRI) in controlled environments. This is fundamental for understanding the link between micrometre-scale tissue properties and DW-MRI signals measured at the millimetre-scale, optimizing acquisition protocols to target microstructure properties of interest, and exploring the robustness and accuracy of estimation methods. However, accurate simulations require substrates that reflect the main microstructural features of the studied tissue. To address this challenge, we introduce a novel computational workflow, CACTUS (Computational Axonal Configurator for Tailored and Ultradense Substrates), for generating synthetic white matter substrates. Our approach allows constructing substrates with higher packing density than existing methods, up to 95% intra-axonal volume fraction, and larger voxel sizes of up to 500μm ³ with rich fibre complexity. CACTUS generates bundles with angular dispersion, bundle crossings, and variations along the fibres of their inner and outer radii and g-ratio. We achieve this by introducing a novel global cost function and a fibre radial growth approach that allows substrates to match predefined targeted characteristics and mirror those reported in histological studies. CACTUS improves the development of complex synthetic substrates, paving the way for future applications in microstructure imaging.
To investigate the cardiovascular system, mathematical modelling and descriptive-analytical methods may be employed in which the various physiological-geometrical-functional parameters have been included. These parameters have been affected by many factors like apparent diffusion coefficient (ADC) and capillary bed. The conceptual relationship between heart rate, mean arterial and venous pressures, and ADC has not yet been fully elucidated. Therefore, introducing an appropriate function in the cardiovascular system is necessary for better diagnostics in medical field, which has been addressed here. A complex Fermi function as pseudo-pressure (RADC) in terms of mmHg sec ml−1 is proposed to assess the effect of the ADC emanating from the capillary bed on the other parameters of the cardiovascular system. It consists of the baroreflex-feedback mechanism on a scheme of differential equations targeting the uncontrolled non-pulsatile cardiovascular system in which the RADC function over time is contained. The modified differential equations were simulated using Matlab software. The simulated results were displayed with a reduction in RADC, the other parameters such as heart rate, mean arterial and venous pressure were increased non-linearly. In general, the diagnostic methods based on the physiological parameters of heart and geometrical structure of blood vessels at various diameters, which might have been characterized, are significant factors in deciding the degree of disease and their proper medical treatment. Our findings may suitably aid in stroke grading and lead to better diagnosis and prediction of estimated recovery time.
A critical review of the applications of porous media in a biological system is conducted in this study. Transport phenomena in porous media are receiving a great deal of attention from many investigators due to their importance in many biomedical applications. Such applications include drug delivery, medical imaging, transport in biological tissues, and porous scaffold for tissue engineering. This chapter is structured in three sections: the first part summarizes pertinent studies in modeling transport phenomena in arteries. The second part focuses on the applications of porous media in modeling endovascular coiling in the treatment of cerebral aneurysms. The third part summarizes the available diffusion models and effective diffusion coefficients associated with brain tissues. Finally, future studies on the applications of porous media are recommended in this review.
Moyamoya disease (MMD) is a chronic and progressive cerebrovascular stenosis or occlusive disease that occurs near Willis blood vessels. Diffusion tensor imaging (DTI) and functional magnetic resonance imaging (fMRI) are used to detect the microstructure of white matter and the function of gray matter, respectively. The damage of these structures will lead to the change of cognitive level in patients with moyamoya disease. In this paper, the principles of DTI and fMRI, their applications and challenges in moyamoya disease are reviewed.
Diffusion imaging (DWI) is considered an optimal technique to detect hyperacute cerebral ischemia and has thus enriched the clinical management of patients with suspected stroke. Researchers have taken this technique beyond with Diffusion Tensor Imaging (DTI)-extracted measures, which have been proposed as biomarkers of stroke progression. A large body of literature report on the correlates between pathophysiological events, such as cytotoxic and vasogenic edema, and diffusion changes in the brain. However, a unified picture of these changes, and their exploration as stroke pathology progression biomarkers, remains to be done. We present here a narrative review on the different pathophysiological events underlying stroke from onset until late subacute stages and its relation to different brain edema forms. Studies included in this review used either DWI and/or DTI analysis in hyperacute (<24 h), acute (1–7 days), early subacute (7–30 days) and/or late subacute (1–6 months) phase of stroke, including human and animal models. Our conclusions are that diffusion measures should be considered as a potential proxy measure for stroke neuroinflammation status, specially in early stages of the disease. Furthermore, we suggest that the choice of diffusion measures and the interpretation of their changes, in both research and clinical settings, need to be linked to the different stroke phases to account correctly for the progression, and eventual resolution, of neuroinflammation.
Magnetic Resonance Imaging (MRI) uses the principle of nuclear magnetic resonance to generate high-resolution images of brain. Due to abundance of water in human body, current MR imaging is based on proton imaging. MRI enables non-invasive structural as well as functional evaluation of brain parenchyma. T1WI provide detailed structural evaluation of brain. Advanced sequences such as Diffusion Weighted Imaging (DWI), MR Perfusion, MR Spectroscopy, Diffusion Tensor Imaging and functional MRI enable the evaluation of metabolic, haemodynamic and cytoarchitecture of brain parenchyma in a non-invasive manner. This book chapter aims to provide insight into basic and various advanced MRI sequences along with its potential applications in neuroimaging.
The synthetic vitamin A derivative, fenretinide (4HPR) was developed in the 1970’s as a means to induce retinoid cancer preventive effects in cells and tissues devoid of the retinoic acid receptor, and has become an important compound for chemoprevention of a variety of cancers such as oral squamous cell carcinoma (OSCC). However, OSCC chemoprevention clinical trials with orally delivered 4HPR have been unsuccessful likely due to extensive first pass metabolism, systemic toxicity, and sub-therapeutic levels of 4HPR at the target site. Local 4HPR delivery vehicles have the potential to deliver therapeutic doses while alleviating any systemic side effects. Limited penetration distance of the drug in tissues, however, is one of the most prevalent challenges with the local delivery approach. To overcome these limitations and to increase drug exposure at the site of action, solubilizers and permeation enhancers were combined with 4HPR in local delivery depots, and their drug release kinetics in vivo and 4HPR’s tissue uptake in presence of solubilizers ex vivo were evaluated. Long-acting release of 4HPR from injectable millicylindrical implants were prepared with poly(lactic-co-glycolic acid) and polyvinyl alcohol (PVA)/sucrose matrices as a function of drug loading and the presence of various excipients to enhance the release of the water-insoluble 4HPR. 4HPR was released from PLGA implants much slower in vivo than in the Tween 80-solubilizing media in vitro, with a 3-week lag phase followed by continuous release of >2 months, and showed some release enhancement by addition of solubilizers. The water-soluble PVA/sucrose implant provided continuous drug release for up to 6 weeks in vivo. These 4HPR-PLGA formulations were further evaluated in an oral cancer xenograph mouse model, and shown to be effective at reducing rate of tumor growth over 10 days. A remarkable solubility enhancing formulation was achieved with 4HPR amorphous solid dispersions (ASDs) prepared with polvinylpyrrolidone (PVP) polymer. The PVP-4HPR ASD was loaded into PLGA implants and evaluated in vivo, and found to substantially improve release kinetics from previous crystalline 4HPR formulations. Tissue binding kinetics was characterized in buccal epithelia and subcutaneous tissues in presence of various solubilizing and permeation enhancing media. Time of exposure, but not solubilizer or permeation enhancers, affected uptake and 4HPR exhibited a five-fold greater binding affinity to buccal epithelia relative to subcutaneous connective tissues. These optimized long-acting 4HPR millicylindrical implants were further evaluated in vivo over 2 weeks in rabbit buccal epithelia, for their ability to enhance drug-tissue distribution. Quantitative Raman spectroscopic imaging was utilized to measure drug-tissue concentration gradients in excised tissue sections. The implants released much faster in the mouth compared to our previous studies in s.c. tissue, and the drug penetration in the buccal tissues (i.e. distance to reach 10% of concentration at implant surface, or C10) was on the order of 0.5- 8 mm for all formulations. The ASD of 4HPR in PLGA provided the greatest drug penetration through tissues, likely as a result of supersaturated drug concentrations next to the implant. Hence, these approaches may be useful for local delivery of 4HPR and OSCC chemoprevention.
Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) is a unique tool to investigate brain microstructure in a cell-specific manner, while neglecting phenomena related to the extracellular environment. In this thesis, we studied DW-MRS in several complementary ways in order to be able to apply this technique in later clinical studies: optimization of the acquisition pipeline and data analysis, reproducibility of the diffusion measures, and histological validation of the DW-MRS metrics as potential useful markers of brain diseases-related microstructural alterations. The thesis is composed of three parts. In the first part, we propose an optimization of the acquisition and of the post-processing procedures for single-voxel DW-MRS experiments in humans, and an evaluation of the feasibility of a DW-semi-LASER sequence for clinical studies at 3 T. Power calculations for the metabolite diffusion measures were reported in order to provide useful information for designing case-control studies in patients with brain diseases. In the second part, we focused on validating DW-MRS metrics using histological measures in two different mouse models of myelinopathy. A strong correlation was found between mIns diffusivity and the astrocyte area fraction confirming the hypothesis that mIns diffusivity can be used as a marker of astrocyte hypertrophy during the inflammatory process. In the last part, we studied the longitudinal evolution of axonal and glial alterations after ischemic stroke in the human brain. We observed the presence of inflammation due to glial reactivity about one month after ischemic stroke and astrocytic reactivity up to about three months after the ischemic stroke.
Following a stroke, the ability to discriminate between areas of non-recoverable tissue and potentially salvageable tissue remains a goal of diagnostic imaging. There have been a number of recent developments both in nuclear medicine and in magnetic resonance imaging (MRI) techniques, which may have potential to achieve this goal. This thesis describes the use of these techniques for the evaluation of focal pathophysiology in a rat model of model cerebral artery occlusion (MCAO). Methods were described to use autoradiographic markers to study cerebral blood flow (99mTc-hexamethylpropylene amine oxime) and cerebral hypoxia (125I-iodoazomycin arabinoside) simultaneously following MCAO in the rat. The uptake of these tracers was compared to MRI measurements of the apparent diffusion coefficient of water (ADC) and to histology. It was shown that the combined use of 125I-IAZA or ADC imaging with perfusion imaging may allow differentiation between areas of oligaemic misery perfusion, ischaemic misery perfusion and ischaemic lesion core. MRI was used to examine the effects of cerebral tissue anisotropy on calculation of the spatial distribution of ischaemia in the rat using ADC measurements. Demonstration of grey matter anisotropy led to the use of rotationally invariant ADC measurements which were shown to improve stroke lesion delineation. To investigate the acute changes in NMR parameters of diffusion, perfusion, T1 and T2 a remote controlled MCAO model in the rat was refined for a vertical 8.5T high field magnet. Combined perfusion and diffusion data distinguish between a "moderately affected area", with reduced perfusion but normal diffusion; and a "severely affected area", in which both perfusion and diffusion were significantly reduced. Two novel MRI observations were reported, namely a decrease in T2 and an increase in T1, both within the first few minutes of ischaemia. A rat model of oligaemic misery perfusion was developed in which a large region of homogeneously reduced blood flow was produced without cytotoxic oedema forming. Early NMR changes in CBF, T1 and T2 were noted without reduction in the ADC value. This approach may provide a model of penumbral flow, which may be of value in studying and evaluating neuroprotection.
This thesis is concerned with the application of three magnetic resonance (MR) techniques in epilepsy: i.) Fluid attenuated inversion recovery prepared (FLAIR) imaging, ii.) diffusion imaging including diffusion tensor imaging (DTI) and iii.) serial and high resolution imaging of the hippocampus. I assessed the clinical value of fast FLAIR in epilepsy in a study involving 128 patients and of 3D FLAIR in a study involving 10 patients. The conspicuity of neocortical lesions and hippocampal sclerosis was increased. New lesions were detected in 5% of patients. The extent of low grade tumours was best assessed on 3D fast FLAIR images. Fast FLAIR was inferior to standard MR techniques for identifying and heterotopia. I applied newly developed, experimental diffusion imaging techniques. In eight studies using different diffusion imaging techniques involving a total of 50 patients and 54 control subjects I investigated the mobility of water molecules in the human epileptic brain in vivo. I used spin echo diffusion imaging in two studies, echo planar imaging (EPI) based DTI in four studies and EPI diffusion imaging in a patient during focal status epilepticus. Finally, in a preliminary study I attempted to use EPI diffusion imaging as a contrast to visualise transient changes associated with frequent lateralizing spikes. Our findings were: i.) diffusion is increased in hippocampal sclerosis suggesting a loss of structural organization and expansion of the extracellular space, ii.) displaying the directionality (anisotropy) of diffusion is superior to standard imaging to visualise tracts, iii.) anisotropy is reduced in the pyramidal tract in patients with hemiparesis and iv.) in the optic radiation in patients with hemianopia after temporal lobectomy suggesting wallerian degeneration, v.) both developmental and acquired structural abnormalities have a lower anisotropy than normal white matter, vi.) diffusion abnormalities in blunt head trauma are widespread and may include regions which are normal on standard imaging, indicating micro structural damage suggestive of diffuse axonal injury, vii.) focal status epilepticus can be associated with a reduced difflision in the affected cortex, viii.) diffusion imaging may be useful as a contrast for event-related (spike triggered) functional MR imaging. With serial MRI I demonstrated hippocampal volume loss in a patient after generalized status epilepticus and with high resolution imaging of an anatomical specimen and a control subject I showed hippocampal layers on MR images. The results presented in this thesis emphasised the flexibility of MR imaging and its ability to demonstrate abnormalities in vivo. FLAIR imaging is now part of the clinical work up of patients with epilepsy. Diffusion imaging has been shown to be superior to standard imaging to visualise tracts which has far-reaching implications for neurological applications. Diffusion imaging also provides an exciting window to study cerebral micro structure in vivo. Serial imaging allows for the first time the visualisation of temporal changes and high resolution imaging has the prospect of demonstrating hippocampal layers in vivo. MR imaging is a constantly progressing technique. It is hoped that this thesis will help to formulate hypotheses for new MR experiments to study the relationship of dysfunction and structural abnormalities.
Background and purpose:
There are sparse data on the microstructural integrity of salvaged penumbral tissue after mechanical thrombectomy of large-vessel occlusions. The aim of the study was to analyze possible microstructural alteration in the penumbra and their association with clinical symptoms as well as angiographic reperfusion success in patients undergoing mechanical thrombectomy.
Materials and methods:
All patients who underwent mechanical thrombectomy for large-vessel occlusions in the anterior circulation and who received an admission CT perfusion together with postinterventional DTIs were included (n = 65). Angiographic reperfusion success by means of modified Thrombolysis in Cerebral Infarction (mTICI) scale and clinical outcome were recorded. Microstructural integrity was assessed by DTI evaluating the mean diffusivity index within the salvaged gray matter of the former penumbra.
Results:
The mean diffusivity index was higher in completely recanalized patients (mTICI 3: -0.001 ± 0.034 versus mTICI <3: -0.030 ± 0.055, P = .03). There was a positive correlation between the mean diffusivity index and NIHSS score improvement (r = 0.49, P = .003) and the mean diffusivity index was associated with midterm functional outcome (r = -0.37, P = .04) after adjustment for confounders. In mediation analysis, the mean diffusivity index and infarction growth mediated the association between reperfusion success and clinical outcomes.
Conclusions:
The macroscopic salvaged penumbra included areas of microstructural integrity changes, most likely related to the initial hypoperfusion. These abnormalities were found early after mechanical thrombectomy, were dependent on angiographic results, and correlated with the clinical outcome. When confirmed, these findings prompt the evaluation of therapies for protection of the penumbral tissue integrity.
Significance
Cerebral malaria (CM) is the deadliest complication of Plasmodium falciparum infection, resulting in a 15 to 25% mortality rate in African children despite antimalarial chemotherapy. Tragically, nearly a fourth of pediatric CM survivors suffer long-term neurological sequelae. There is an urgent public health and humanitarian need for therapies for CM. In a mouse model of CM, we used magnetic resonance imaging (MRI) to monitor infected mice longitudinally as CM progressed and noninvasively demonstrate that the edema and blood–brain barrier dysfunction, which ultimately result in death, are rapidly reversed by treatment with the glutamine antagonist JHU-083. The similarities between CM MRI shown in mice and those reported in children and adults suggest that glutamine antagonists may be effective CM therapies.
Diffusion-weighted magnetic resonance spectroscopy (DW-MRS) allows to uniquely characterize the brain tissue in vivo by quantifying the diffusion of brain metabolites. In contrast with water, many brain metabolites are predominantly intracellular, and some metabolites are preferentially found in specific brain cell types, e.g., neurons and glia. Given the microstructural sensitivity of diffusion-encoding filters, investigation of metabolite diffusion properties using DW-MRS can provide exclusive cell and compartment-specific information. Since many developmental processes, such as plasticity and aging, or pathological processes such as neurological diseases are characterized by modulations of specific cellular types and their microstructures, and since water signal is not representative of any specific compartment, metabolite signals can serve as biomarkers with enhanced specificity. Furthermore, since many models and assumptions are used for quantification of water diffusion, metabolite diffusion may serve to generate a-priori information for model selection.
In this chapter, we survey the state-of-the-art methods that have been developed for the advanced analysis of DW-MRS data and discuss the potential relevance of DW-MRS for elucidating brain microstructure in vivo. Some examples are reported and discussed, showing that when accurate data on the diffusion of multiple metabolites is combined with accurate computational and geometrical modelling, DW-MRS can provide unique and accurate cell-specific information on the intracellular structure of brain tissue.
Magnetic resonance imaging (MRI) is a technique based on the contents and relaxation features of water in tissues. In basic MRI sequences, diffusion phenomenon of water molecules is not taken into account although it has a notable influence in the relaxation times, and therefore in the signal intensity of images. In fact, MRI techniques that take advantage of water diffusion have experienced a huge development in last years. Diffusion-weighted imaging (DWI) has spectacularly evolved reaching nowadays a great impact both in clinical and preclinical imaging—especially in the neuroimaging field—and in basic research. We present here a protocol to perform DWI studies in a high-field preclinical setup.
Oxygen monitoring is a topic of exhaustive research due to its central role in many biological processes, from energy metabolism to gene regulation. The ability to monitor in vivo the physiological distribution and the dynamics of oxygen from subcellular to macroscopic levels is a prerequisite to better understand the mechanisms associated with both normal and disease states (cancer, neurodegeneration, stroke, etc.). This chapter focuses on magnetic resonance imaging (MRI) based techniques to assess oxygenation in vivo. The first methodology uses injected fluorinated agents to provide quantitative pO2 measurements with high precision and suitable spatial and temporal resolution for many applications. The second method exploits changes in endogenous contrasts, i.e., deoxyhemoglobin and oxygen molecules through measurements of T2* and T1, in response to an intervention to qualitatively evaluate hypoxia and its potential modulation.
We review the hemodynamic, metabolic and cellular parameters affected during early ischemia and their changes as a function of approximate cerebral blood flow ( CBF) thresholds. These parameters underlie the current practical definition of an ischemic penumbra, namely metabolically affected but still viable brain tissue. Such tissue is at risk of infarction under continuing conditions of reduced CBF, but can be rescued through timely intervention. This definition will be useful in clinical diagnosis only if imaging techniques exist that can rapidly, and with sufficient accuracy, visualize the existence of a mismatch between such a metabolically affected area and regions that have suffered cell depolarization. Unfortunately, clinical data show that defining the outer boundary of the penumbra based solely on perfusion-related thresholds may not be sufficiently accurate. Also, thresholds for CBF and cerebral blood volume ( CBV) differ for white and gray matter and evolve with time for both inner and outer penumbral boundaries. As such, practical penumbral imaging would involve parameters in which the physiology is immediately displayed in a manner independent of baseline CBF or CBF threshold, namely pH, oxygen extraction fraction ( OEF), diffusion constant and mean transit time ( MTT). Suitable imaging technologies will need to meet this requirement in a 10-20 min exam.
MRI in neuroradiology has evolved in the last 30 years, becoming faster, more precise, and more specific. The latest additions, including magnetic resonance spectroscopy (MRS), diffusion imaging, diffusion tensor imaging, functional MRI, and dynamic susceptibility contrast perfusion imaging, have expanded the applications for MR imaging. Currently, fluid attenuation inversion recovery (FLAIR) imaging, thin-section 3D volumetric imaging with spoiled gradient techniques, and the others mentioned above permit not only the precise localization of brain lesions, but also the evaluation of their metabolic profile, their location relative to eloquent regions of the cortex and subcortical white matter, and the relative blood volume and permeability of the vasculature that supplies the lesion. Thus, cellular, vascular, functional and anatomic information are obtained in one examination session and are available to treating physicians in their office, operating room, or radiation therapy suite.
Contrast in magnetic resonance imaging (MRI) is generated by exploiting a variety of physicochemical properties. Conventional clinical MRI techniques are largely based upon disease-induced changes in water relaxation, but these have been complemented by a number of other approaches, including a sensitization to the diffusion of water. It has been shown that diffusion-weighted (DW) imaging can be used to advantage in the diagnosis of a number of pathologies that are undetectable using standard imaging protocols. Moreover, DW imaging can provide information concerning the nature of the pathology, in addition to the spatial information that is obtained from the image per se. This chapter starts with a brief description of the diffusion phenomenon and nuclear magnetic resonance (NMR) methods for measuring diffusion coefficients. This is followed by sections devoted to some theoretical and instrumental aspects of DW imaging. The remainder of the chapter is concerned with some biomedical applications of DW imaging, with an emphasis on cerebral pathophysiology. No attempt has been made to provide an exhaustive review of the literature on DW imaging. On the contrary, we have identified a few studies that specifically serve to illustrate its potential application to neuroscience.
A method is outlined that completely separates intracellular and extracellular information in NMR spectra of perfused cells. The technique uses diffusion weighting to exploit differences in motional properties between intra- and extracellular constituents. This allows monitoring of intracellular metabolism, and of transport of small drugs and nutrients through the cell membrane, under controlled physiological conditions. As a first example, proton spectra of drug-resistant MCF-7 human breast cancer cells are studied, and uptake of phenylalanine is monitored.
Molecular diffusion and microcirculation in the capillary network result in a distribution of phases in a single voxel in the presence of magnetic field gradients. This distribution produces a spin-echo attenuation. The authors have developed a magnetic resonance (MR) method to image such intravoxel incoherent motions (IVIMs) by using appropriate gradient pulses. Images were generated at 0.5 T in a high-resolution, multisection mode. Diffusion coefficients measured on images of water and acetone phantoms were consistent with published values. Images obtained in the neurologic area from healthy subjects and patients were analyzed in terms of an apparent diffusion coefficient (ADC) incorporating the effect of all IVIMs. Differences were found between various normal and pathologic tissues. The ADC of in vivo water differed from the diffusion coefficient of pure water. Results were assessed in relation to water compartmentation in biologic tissues (restricted diffusion) and tissue perfusion. Nonuniform slow flow of cerebrospinal fluid appeared as a useful feature on IVIM images. Observation of these motions may significantly extend the diagnostic capabilities of MR imaging.
Diffusion-weighted, echo-planar imaging (EPI) was used to map regional changes in the apparent diffusion coefficient (ADC) during experimental focal ischemia in the rat brain following permanent middle cerebral arterial occlusion (MCAO). Sixteen 64 x 64 diffusion-weighted EPIs were acquired in 32 s with successively increasing amplitudes of the diffusion-sensitive gradient pulses. A linear least-squares regression algorithm was used to fit 15 of the 16 two-dimensional matrices, on a pixel-by-pixel basis, to solve for the slope from which the ADC value was calculated. The correlation coefficient of the fit, R2, was used to filter the final ADC maps, and the ADCs were then scaled appropriately to be displayed in a 256 gray level format. Ranges (bins) of 0.05 x 10(-3) mm2/s were then grouped and color coded to qualify and quantify the evolution of ischemia in the MCA territory. The percentage of area in the ischemic and contralateral hemispheres in seven ADC bins were calculated at 30, 60, and 120 min after MCAO for 10 animals and demonstrated a significant increase in ADC bins below 0.45 x 10(-3) mm2/s and a decrease in bins above 0.50 x 10(-3) mm2/s over time. The postmortem infarct area, as measured by TTC staining, was highly correlated with the portion of the ischemic hemisphere falling below ADC values of 0.55 x 10(-3) mm2/s at 2 h after stroke onset. These studies suggest that focally ischemic brain tissue can be quantitatively subdivided according to ADC values and that ADC values below 0.55 x 10(-3) mm2/s 2 h following ischemia highly predict infarction in a rat permanent occlusion stroke model.
Background and purpose:
Diffusion-weighted magnetic resonance imaging has been shown to be particularly suited to the study of the acute phase of cerebral ischemia in animal models. The studies reported in this paper were undertaken to determine whether this technique is sensitive to the known ischemic thresholds for cerebral tissue energy failure and disturbance of membrane ion gradients.
Methods:
Diffusion-weighted images of the gerbil brain were acquired under two sets of experimental conditions: as a function of cerebral blood flow after controlled graded occlusion of the common carotid arteries (partial ischemia), as a function of time following complete bilateral carotid artery occlusion (severe global ischemia), and on deocclusion after 60 minutes of ischemia.
Results:
During partial cerebral ischemia, the diffusion-weighted images remained unchanged until the cerebral blood flow was reduced to 15-20 ml.100 g-1.min-1 and below, when image intensity increased as the cerebral blood flow was lowered further. This is similar to the critical flow threshold for maintenance of tissue high-energy metabolites and ion homeostasis. After the onset of severe global cerebral ischemia, diffusion-weighted image intensity increased gradually after a delay of approximately 2.5 minutes, consistent with complete loss of tissue adenosine triphosphate and with the time course of increase in extracellular potassium. This hyperintensity decreased on deocclusion following 60 minutes of ischemia.
Conclusions:
The data suggest that diffusion-weighted imaging is sensitive to the disruption of tissue energy metabolism or a consequence of this disruption. This raises the possibility of imaging energy failure noninvasively. In humans, this could have potential in visualizing brain regions where energy metabolism is impaired, particularly during the acute phase following stroke.
A general treatment of time‐dependent (transient) diffusion coefficients in a system of parallel planar barriers of arbitrary permeability has been performed, with emphasis on the results expected for NMR pulsed‐field‐gradient, spin‐echo measurements. This is the first such derivation for permeable barriers of any geometry. The calculated distribution functions and diffusion coefficients are in agreement with expectations in most of the limiting cases tried, except that an unexplained dependence of the diffusion coefficients on the magnitude of the field gradient, even at long diffusion times, was found. The application of the results to the interpretation of experimental results is discussed.
We have developed an approximate expression for the spin–echo attenuation as function of the diffusion time in a pulsed‐gradient experiment on specimens containing regularly spaced barriers of arbitrary permeability. The expression is a modification of the exact solution for impermeable barriers, and is simple enough to permit use in curve‐fitting programs.
The Bloch—Torrey equations are modified to include the case of anisotropic, restricted diffusion and flow. The problem of solving these modified equations for the amplitude of a spin echo in a time-dependent magnetic-field gradient subject to restricting boundary conditions is discussed. This problem is solved for a number of selected cases. In particular, it is found that a magnetic-field gradient applied in short, intense pulses is effective in defining the time during which nuclear displacements take place. A simplified equation, suitable for the pulsed-gradient experiment, is presented and solved for two different examples of systems showing restricted diffusion. A procedure for analyzing the data from pulsed-gradient measurements is suggested, and its merits are discussed. Suggestions are made of systems which may well be expected to show restricted, anisotropic diffusion or interesting flow properties.
The occlusion of the middle cerebral artery in cat brain was used as an experimental stroke model to investigate the physical basis of the recently reported lowered diffusion constant of water in acute infarcted brain tissue (Moseley et al., Magn. Reson. Med.14, 330, 1990). The original findings were confirmed in this study of 12 animals investigated with the diffusion-sensitized stimulated echo sequence. The following additional results were obtained: First, the onset of significant lowering of the diffusion constant in the stroke area varied significantly (up to 2.5 h depending on the animal). Second, the affected area is much more clearly outlined in diffusion-weighted images than in T2,-weighted images, even in the period between 3 to 12 h following occlusion. Third, for diffusion times between 50 and 2000 ms, the diffusion constant of water is independent of diffusion time in healthy tissue, as well as in the stroke area. Fourth, the diffusion anisotropy is similar in healthy and in stroke area and remains similar regardless of the diffusion time used. © 1991 Academic Press, Inc.
NMR imaging of molecular self-diffusion is demonstrated for the first time using stimulated-echo (STE) NMR signals. Stimulated-echo acquisition-mode (STEAM) imaging has been described in a preceding paper. It is based on a 90°-t1-90°-t2-90°-t3 rf excitation sequence and relies on the detection of the STE signal appearing at t3 = t1. By incorporating a pair of pulsed magnetic field gradients into the first and third intervals of the STEAM sequence, the effect of molecular self-diffusion on NMR images may be qualitatively demonstrated. A variation of the strength of the gradient pulses and/or the diffusion time, i.e., the length of the second interval, yields a series of diffusion weighted images which allows the calculation of a synthetical image solely displaying the self-diffusion coefficient. Experimental results on 1H NMR images of phantoms are presented which clearly demonstrate the potential of diffusion imaging as a new tool in medical diagnosis as well as for nonmedical applications.
Water diffusion permeability of human erythrocytes has been measured by NMR using a pulsed magnetic field gradient technique. The measurement of exchange rates was based on restricted diffusion of water molecules within red blood cells. This method avoids addition of paramagnetic ions, such as Mn2+, and is used in vivo. The mean lifetime of water insed human erythrocytes was found to be 17 ms at 24 degrees C. A sulfhydryl reagent, known to inhibit water osmotic permeability, reduced significantly water diffusion across the red cell membrane.
Focal brain ischemia was induced by middle cerebral artery occlusion in the rat. The volume of cerebral damage was determined 2 days later by MRI in vivo and in the same animals histologically. The edema volume as measured by MRI and the histologically determined infarction was highly correlated. As a consequence, the neuroprotective effect of the N-methyl-D-aspartate (NMDA) receptor antagonists CGP 40116 and MK 801 were similar with both methods. Excitotoxic neurodegeneration in the rat striatum was induced by direct injection of quinolinic acid. The degree of damage was evaluated in vivo 1 day later by quantitative MRI, and 7 days later by measuring the activities of neuronal marker enzymes choline acetyltransferase and glutamic acid decarboxylase. Striatal damage assessed using the three approaches was highly correlated. Cerebroprotective efficacy of the NMDA receptor antagonist CGP 40116 was indistinguishable based on all methods. MRI was more reproducible than the enzymatic methods and was faster and simpler than histologic examination for routine analysis of excitotoxic damage and cerebroprotection in vivo in a pharmaceutical research environment.
We examined serial changes of diffusion- (DWI) and T2-weighted (T2WI) magnetic resonance images 30 minutes to 3 hours after intraluminal suture occlusion of the middle cerebral artery (MCA) in eight rats and after sham occlusion in four. We correlated the abnormal areas on DWI and T2WI with postmortem areas of infarction determined by 2,3,5-triphenyltetrazolium chloride (TTC), 24 hours after the operation. The 30-minute DWI in each MCA-occluded rat demonstrated increased signal intensity in the ipsilateral MCA territory, while T2WI showed no changes. At 3 hours, the ipsilateral DWI signal intensity increased further and the area of abnormality slightly increased. In some animals, the 3-hour T2WI disclosed an area of hyperintensity significantly smaller than that seen on the 30-minute DWI. TTC staining demonstrated an extensive MCA infarction in all rats with permanent MCA occlusion, confirmed by hematoxylin and eosin staining. The percent infarcted area of coronal brain sections, as determined by TTC staining, correlated significantly with areas on similar DWI sections at both 30 minutes and 3 hours. Sham-occluded control animals did not display any changes on DWI, T2WI, or TTC staining. The present study suggests that DWI is a very sensitive modality for detecting early ischemic brain injury, being highly correlated with post-mortem area of infarction, and may be useful to assess pharmacologic intervention.
The aim of this study was to measure apparent diffusion coefficients in rat brain tissue exposed to ouabain, glutamate, and N-methyl-D-aspartate and to compare them with apparent diffusion coefficients found in acute cerebral ischemia.
The apparent diffusion coefficient was measured using magnetic resonance microscopy in four groups of Sprague-Dawley rats after occlusion of the right middle cerebral artery and ipsilateral common carotid artery (n = 7), after ouabain exposure (n = 6), during glutamate exposure (n = 7), or during N-methyl-D-aspartate exposure (n = 3). Ouabain, glutamate, and N-methyl-D-aspartate were applied via an intracerebrally implanted microdialysis membrane.
Three hours after the induction of focal cerebral ischemia, a 33% reduction in the apparent diffusion coefficient was observed in the right dorsolateral corpus striatum and olfactory cortex. After ouabain exposure, reductions in the apparent diffusion coefficient were observed within a 1,500-microns radius of the microdialysis membrane. Quantitative analysis revealed that apparent diffusion coefficient values in ischemic and ouabain-exposed tissue fell within the same range. Glutamate and N-methyl-D-aspartate reduced the brain tissue apparent diffusion coefficient by 35% and 40%, respectively.
On the basis of these findings, we conclude that ischemia-induced apparent diffusion coefficient reductions are likely caused by a shift of extracellular to intracellular water.
Diffusion-weighted magnetic resonance imaging has been shown to be particularly suited to the study of the acute phase of cerebral ischemia in animal models. The studies reported in this paper were undertaken to determine whether this technique is sensitive to the known ischemic thresholds for cerebral tissue energy failure and disturbance of membrane ion gradients.
Diffusion-weighted images of the gerbil brain were acquired under two sets of experimental conditions: as a function of cerebral blood flow after controlled graded occlusion of the common carotid arteries (partial ischemia), as a function of time following complete bilateral carotid artery occlusion (severe global ischemia), and on deocclusion after 60 minutes of ischemia.
During partial cerebral ischemia, the diffusion-weighted images remained unchanged until the cerebral blood flow was reduced to 15-20 ml.100 g-1.min-1 and below, when image intensity increased as the cerebral blood flow was lowered further. This is similar to the critical flow threshold for maintenance of tissue high-energy metabolites and ion homeostasis. After the onset of severe global cerebral ischemia, diffusion-weighted image intensity increased gradually after a delay of approximately 2.5 minutes, consistent with complete loss of tissue adenosine triphosphate and with the time course of increase in extracellular potassium. This hyperintensity decreased on deocclusion following 60 minutes of ischemia.
The data suggest that diffusion-weighted imaging is sensitive to the disruption of tissue energy metabolism or a consequence of this disruption. This raises the possibility of imaging energy failure noninvasively. In humans, this could have potential in visualizing brain regions where energy metabolism is impaired, particularly during the acute phase following stroke.
Rapid MRI of the molecular diffusion of water demonstrated cerebral infarcts in 32 patients. We studied these patients at various times following the onset of ischemic symptoms and found that diffusion-weighted imaging revealed the infarcts sooner than conventional T2-weighted spin-echo imaging did; four hyperacute infarcts were shown only by diffusion-weighted imaging. Acute infarcts had lower apparent diffusion coefficients (ADCs) than noninfarcted regions did. This relative difference in ADC reached a nadir in the first 24 hours and rose progressively thereafter. Chronic infarcts showed a relative increase in diffusion and were readily distinguishable from acute infarcts. The technique takes less than 2 minutes to apply using a standard 1.5-tesla scanner in the clinical setting. Diffusion-weighted imaging has the potential to play a role in improving the early anatomic diagnosis of stroke and therefore in the development and implementation of early stroke interventions.
Diffusion-weighted magnetic resonance imaging (DWI) can quantitatively display focal brain abnormalities within minutes after the onset of ischemia. We performed the present study to determine the effects of 1 and 2 hours of temporary ischemia on DWI.
We examined DWI and T2-weighted magnetic resonance images (T2WI) during and after 1 and 2 hours of temporary middle cerebral artery occlusion in rats (n = 10 for each group). In a subgroup of four animals from each group, we employed perfusion magnetic resonance imaging to monitor cerebral perfusion. Neurological outcome and infarct size after survival for 24 hours were compared between the groups and correlated with DWI and T2WI studies.
Perfusion studies qualitatively documented hypoperfusion and reperfusion during and after temporary occlusion. Lesion size on DWI during reperfusion was significantly less than that during ischemia for 1 (55% decline, p less than 0.02) but not 2 hours of occlusion. The DWI signal intensity ratio (intensity compared with that in the contralateral homologous area) just before withdrawal of the occluder was significantly less in regions where the hyperintensity disappeared after withdrawal than in regions with persistent hyperintensity (p less than 0.002). The T2WI studies revealed few or no abnormalities, except after 2 hours of occlusion. The neurological outcome was significantly better in the 1-hour than in the 2-hour group (p less than 0.05). Postmortem infarct volume was significantly smaller in the 1-hour group than in the 2-hour group (p less than 0.05). The postwithdrawal DWI accurately predicted infarct size (R = 0.96, p less than 0.0001).
The present study indicates that DWI can rapidly display not only irreversible but also reversible ischemic brain damage and enhances the importance of DWI as a diagnostic modality for stroke.
MR diffusion imaging was performed to investigate changes in water diffusion in patients with cerebral infarction.
Diffusion maps of the apparent diffusion coefficient (ADC) were created to show local water mobility in the brain tissue in 15 patients. These ADC maps were compared with conventional T2-weighted images.
Distinct subregions with different water diffusions were detected, even when the infarcted area appeared homogeneous on a T2-weighted image. The results also show that stroke lesions of the same age can have very different water diffusions. A trend towards an increasing diffusion coefficient in a lesion during the first several days following an acute event was observed in a group of patients imaged at multiple timepoints.
The measurement of diffusion coefficients in vivo now offers an opportunity for greater understanding of the biophysical changes that occur during the evolution of infarction in humans.
Computer simulation is used to assess the precision and accuracy of diffusion and perfusion parameters derived from a set of gradient-sensitized images. Under ideal experimental conditions, a moderate signal-to-noise level (ca. 40) suffices to estimate diffusion coefficients to within 20% relative precision. However, estimation of a typical cerebral perfusion fraction of 5% to within 20% relative precision requires signal-to-noise levels of ca. 400. Simulations also show that systematic errors in perfusion fraction estimation, as well as underestimation of the uncertainties in perfusion parameters (by chi-squared analysis), will be found at moderate signal-to-noise levels.
The application of stimulated echo acquisition mode (STEAM) sequences for NMR imaging of diffusion is especially suited for spins with T1 much greater than T2 as, e.g., encountered in proton NMR studies of biological systems. Molecular self-diffusion coefficients may be calculated from a set of diffusion-weighted images acquired with different gradient strengths. A variation of the diffusion time allows the determination of restricted and/or anisotropic diffusion in cellular systems ranging from plants to humans. Problems associated with the presence of unavoidable macroscopic motions in vivo are demonstrated in diffusion studies of human brain. Motion ghosting in diffusion-weighted images may be overcome by means of a high-speed STEAM sequence yielding single-shot images within subsecond acquisition times.
Cat brain images sensitized to incoherent motion by additional gradient pulses were obtained on a 4.7 T magnetic resonance unit equipped with shielded gradient coils. The apparent diffusion coefficient of water in gray and white matter was accurately determined and imaged from the signal attenuation curve obtained as a function of gradient strength. Contrast in calculated diffusion images differed from typical T2-weighted contrast. Furthermore, in gray matter and in areas containing flowing CSF the attenuation curve was found to be biexponential. These results are interpreted in terms of a simple voxel model with microcirculation and diffusion contributions.
We studied the effect of focal cerebral ischemia on the "state" of brain water using proton nuclear magnetic resonance imaging. Focal cerebral ischemia was induced in five halothane-anesthetized rats via tandem occlusion of the left common carotid artery and the left middle cerebral artery. The proton transverse relaxation time, the proton density, and the water diffusion coefficient were measured at various times from the same region of brain tissue from 1.5 to 168 hours after occlusion. Early measurements indicated significant changes in the transverse relaxation time (p = 0.004) and water diffusion coefficient (p = 0.002) of ischemic brain tissue compared with a homologous region from the contralateral hemisphere. However, the transverse relaxation time, proton density, and water diffusion coefficient in ischemic brain tissue showed different temporal evolutions over the study period. Diffusion coefficient weighting was superior to relaxation time and proton density weighting for the visualization of early cerebral ischemia. Our data suggest that nuclear magnetic resonance imaging is sensitive in detecting changes in proton-associated parameters during early cerebral ischemia and confirm significant changes (p less than or equal to 0.01) in the temporal evolution of transverse relaxation times, proton densities, and diffusion coefficients following middle cerebral artery occlusion.
The sensitivity of diffusion-weighted MRI was compared to that of T2-weighted MRI following temporary middle cerebral artery occlusion (MCA-O) for 33 min followed by 4 h of reperfusion in rats. Diffusion-weighted spin-echo images using strong gradients (b value of 1413 s/mm2) demonstrated a significant increase in signal intensity in ischemic regions as early as 14 min after onset of ischemia in comparison to the normal, contralateral hemisphere (p less than 0.05). This hyperintensity returned to baseline levels during reperfusion. T2-weighted images showed no evidence of brain injury during the temporary occlusion. In three rats subjected to permanent MCA-O, diffusion-weighted MRI demonstrated an increased signal intensity on the first image following occlusion and continued to increase during the 4-h observation period. T2-weighted images failed to demonstrate significant injury until approximately 2 h after MCA-O. Signal intensity ratios of ischemic to normal tissues were greater in the diffusion-weighted images than in the T2-weighted MR images at all time points (p less than 0.05). Close anatomical correlation was found between the early and sustained increase in diffusion-weighted MRI signal intensity and localization of infarcts seen on post-mortem histopathology.
We evaluated the temporal and anatomic relationships between changes in diffusion-weighted MR image signal intensity, induced by unilateral occlusion of the middle cerebral artery in cats, and tissue perfusion deficits observed in the same animals on T2-weighted MR images after administration of a nonionic intravascular T2 shortening agent. Diffusion-weighted images obtained with strong diffusion-sensitizing gradient strengths (5.6 gauss/cm, corresponding to gradient attenuation factor, b, values of 1413 sec/mm2) displayed increased signal intensity in the ischemic middle cerebral artery territory less than 1 hr after occlusion, whereas T2-weighted images without contrast usually failed to detect injury for 2-3 hr after stroke. After contrast administration (0.5-1.0 mmol/kg by Dy-DTPA-BMA, IV), however, T2-weighted images revealed perfusion deficits (relative hyperintensity) within 1 hr after middle cerebral artery occlusion that corresponded closely to the anatomic regions of ischemic injury shown on diffusion-weighted MR images. Close correlations were also found between early increases in diffusion-weighted MR image signal intensity and disrupted phosphorus-31 and proton metabolite levels evaluated with surface coil MR spectroscopy, as well as with postmortem histopathology. These data indicate that diffusion-weighted MR images more accurately reflect early-onset pathophysiologic changes induced by acute cerebral ischemia than do T2-weighted spin-echo images.
Diffusion-weighted MR images were compared with T2-weighted MR images and correlated with 1H spin-echo and 31P MR spectroscopy for 6-8 h following a unilateral middle cerebral and bilateral carotid artery occlusion in eight cats. Diffusion-weighted images using strong gradient strengths (b values of 1413 s/mm2) displayed a significant relative hyperintensity in ischemic regions as early as 45 min after onset of ischemia whereas T2-weighted spin-echo images failed to clearly demonstrate brain injury up to 2-3 h postocclusion. Signal intensity ratios (SIR) of ischemic to normal tissues were greater in the diffusion-weighted images at all times than in either TE 80 or TE 160 ms T2-weighted MR images. Diffusion- and T2-weighted SIR did not correlate for the first 1-2 h postocclusion. Good correlation was found between diffusion-weighted SIR and ischemic disturbances of energy metabolism as detected by 31P and 1H MR spectroscopy. Diffusion-weighted hyperintensity in ischemic tissues may be temperature-related, due to rapid accumulation of diffusion-restricted water in the intracellular space (cytotoxic edema) resulting from the breakdown of the transmembrane pump and/or to microscopic brain pulsations.
The diffusion behavior of intracranial water in the cat brain and spine was examined with the use of diffusion-weighted magnetic resonance (MR) imaging, in which the direction of the diffusion-sensitizing gradient was varied between the x, y, and z axes of the magnet. At very high diffusion-sensitizing gradient strengths, no clear evidence of anisotropic water diffusion was found in either cortical or subcortical (basal ganglia) gray matter. Signal intensities clearly dependent on orientation were observed in the cortical and deep white matter of the brain and in the white matter of the spinal cord. Greater signal attenuation (faster diffusion) was observed when the relative orientation of white matter tracts to the diffusion-sensitizing gradient was parallel as compared to that obtained with a perpendicular alignment. These effects were seen on both premortem and immediate postmortem images obtained in all axial, sagittal, and coronal views. Potential applications of this MR imaging technique included the stereospecific evaluation of white matter in the brain and spinal cord and in the characterization of demyelinating and dysmyelinating diseases.
This review of water transport measurement in normal human erythrocytes attempts to harmonize discordant results obtained under diverse study conditions with two different techniques: nuclear magnetic resonance (NMR) and radioactive tracer (THO) diffusion. Natural aggregation of red cells into rouleaux appeared to cause most of the variation among results from NMR experiments. The remainder of the discrepancy was attributed to the use of inappropriate mathematical approximations of the two-site exchange equations, differences in blood storage time, and failure to adjust NMR calculations for the nonwater protons. Differences in hematocrit, frequency-magnetic field strength, or NMR pulse technique played no apparent role in the disparity among NMR reports. When these confounding factors were removed, diffusion results obtained by NMR or by influx or bulk diffusion of radioactive tracer agreed within a relatively narrow range of values. These techniques place the mean lifetime of water inside fresh normal human erythrocytes at room temperature (20-25 degrees C) between the extremes of 9.8 and 14 ms, where the uncorrected range was previously 9.8-21.7 ms. This new range of water exchange times corresponds to a range of diffusional permeability between 3.3 and 4.7 x 10(-3) cm/s.
The pathophysiological chain of events occurring during cerebral ischemia is still poorly understood on a molecular level. Therefore, an in vitro model to study glial swelling mechanisms, using C6 glial cells under controlled extracellular conditions, has been established. Flow cytometry serves to determine even small cell volume changes. In this report, the effects of anoxia and acidosis on glial swelling are summarized. Anoxia alone, or in combination with iodoacetate to inhibit anaerobic glycolysis, did not cause an increase of glial volume for up to 2 h. Acidification of the incubation medium below pH 6.8, on the other hand, was immediately followed by cell swelling to 115% of normal. Amiloride or the absence of bicarbonate and Na+ in the medium significantly reduced glial swelling. The data support the contention that swelling results from an activation of the Na+/H+-antiporter to control intracellular pH. It is suggested that swelling in an ischemic penumbra is promoted by this mechanism. Therapeutic approaches to control cerebral pH might be useful to protect brain tissue in cerebral ischemia.
1. Corneal endothelial cell membrane electrical resistance is estimated at about 400 M omega by using intracellular micro-electrodes. 2. If all ion diffusion across the endothelium were transcellular, electrical resistance of the endothelial monolayer would be about 1300 omega cm2, as there are about 3000 cells mm-2. 3. Measured endothelial monolayer resistance is 12.7 +/- 0.8 omega cm2 (mean +/- S.E., n = 6), which indicates that about 99% of ion diffusion does not cross the transcellular pathway, but must pass through the paracellular route. Arguments are presented which suggest that the proportion may be even higher. 4. Endothelial passive ion permeabilities are about the same as corneal stromal passive ion permeabilities. 5. Stromal water diffusional permeability is about the same as stromal ion permeability, after allowance is made for free diffusion coefficients. In contrast, endothelial water diffusional permeability is so high as to be unmeasurable. 6. It is concluded that ions diffuse across the corneal endothelium through the paracellular route, and that water diffuses across the endothelium mainly through the transcellular route.
With the recent development of nuclear magnetic resonance (NMR) imaging it is important to characterise and understand the NMR response of tissues. There are several reasons why such characterisation of tissues using NMR parameters would be useful. It may provide a helpful diagnostic guide and could lead to a deeper understanding of the underlying processes responsible for many pathological and physiological states of tissues. For several years, hydrogen density, spin-lattice relaxation and spin-spin relaxation maps of objects have been obtained using the NMR imaging technique. The authors have developed a method for the spatial mapping of an additional NMR parameter, the molecular translational diffusion coefficient D. In addition the technique will permit the measurement of perfusion and blood flow rates.
The extracellular space (ECS) of the cerebral cortex in the cat was estimated by methods of electrical impedance measurements and concentration profiles of radioactively labeled compounds following subarchnoid (SA) perfusion. Taking various factors into consideration the space was found to be between 15 and 20% and unchanged when the temperature of the cortex was decreased from 37 to 15C. However, the rate of cerebrospinal fluid (CSF) formation, as determined by SA and ventriculocisternal (VC) perfusion, was found to be markedly reduced by hypothermia.
The anisotropy of the water diffusion tensor inside brain causes contrast in diffusion images, which depends on the relative orientation of the diffusion gradients and the subject. Because the trace of a tensor is invariant upon rotation, measurement of this trace can reduce the orientation effect. A family of imaging pulse sequences is presented in which the signal intensity is weighted by the trace of the diffusion tensor in a single scan. The methods are demonstrated for chicken gizzard in several orientations with respect to the gradient frame of reference, and for ischemic injury in cat brain after middle cerebral artery occlusion. The sensitivity of the techniques to the presence of background gradients is measured and discussed in detail. As a result, pulse sequences are suggested that provide reliable diffusion constants in both homogeneous and inhomogeneous magnetic fields. The efficiency of the techniques for clinical application is also evaluated.
Changes in the diffusion constant of water during reversible brain ischemia and cardiac arrest were monitored with a 10-s time resolution. Results (five cats, three rats) indicate that these changes are reversible and that the bulk of the changes are not caused by temperature or motion related to brain pulsations and blood flow. The rapid time course of the changes corresponds to the known time course for changes in energy state, signal transduction, and ionic homeostasis.
Early detection of regional cerebral ischemia in cats: comparison of diffusion-and T2-weighted MRI and spectroscopy
- Weintein
Weintein, Early detection of regional cerebral ischemia in cats: comparison of diffusion-and T2-weighted MRI and spectroscopy. Mugn. Reson. Med. 14, 330-346 (1990).
MRI as-sessment of histologically documented focal cerebral ische-mia
- J A Dreski
- R J Helpern
- Z X Ordige
- L C Qing
- M Rodolosi
- K M A Chopp
- Welch
Dreski, J. A. Helpern, R. J. Ordige, Z. X. Qing, L. C. Rodolosi, M. Chopp, K. M. A. Welch, MRI as-sessment of histologically documented focal cerebral ische-mia, in " Book of Abstracts: SMRM, 1992, " p. 912.
Fiber orientation map-ping in an anisotropic medium with NMR diffusion spec-troscopy, in " Book of Abstracts
- P J Basser
- J Matiello
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